Dibenzofuranyl-aminoalcohols

ABSTRACT

COMPOUNDS OF THE FORMULA 2-(NB-Y-CH(-OH)-)DIBENZOFURAN     WHICH ARE USEFUL AS INTERMEDIATES IN THE PREPARATION OF THE FOREGOING HYPOTENSIVE AGENTS AND ALSO IN SOME CASES EXHIBIT HYPOTENSIVE, SEDATIVE AND MUSCLE RELAXANT ACTIVITY AND PROCESSES FOR THE PREPARATION OF THE FOREGOING COMPOUNDS. IN THE FOREGOING FORMULAE, NB IS A PRIMARY OR SECONDARY AMINO RADICAL AND Y IS (LOWER) ALKYLENE.   2-(NB-Y-CO-)DIBENZOFURAN   WHICH POSSESS HYPOTENSIVE ACTIVITY AND ARE USEFUL FOR TREATING HYPERTENSION IN MAMMALS AND COMPOUNDS OF THE FORMULA

United States Patent 3,701,786 DIBENZOFURANYL-AMINOALCOHOLS Harvey B.Hopps, West Allis, Wis., Dennis Jackman,

University, Miss., and John H. Biel, Lake Blulf, Ill., lassiglvlt rrs toAldrich Chemical Company, Inc., Milwauee, is. No Drawing.Continuation-impart of application Ser. No. 693,765, Dec. 27, 1967,which is a continuation-in-part of application Ser. No. 605,995, Dec.30, 1966, which which are useful as intermediates in the preparation ofthe foregoing hypotensive agents and also in some cases exhibithypotensive, sedative and muscle relaxant activity and processes for thepreparation of the foregoing compounds. In the foregoing formulae, NB isa primary or secondary amino radical and Y is (lower)alkylene.

CROSS-REFERENCE TO RELATED APPLICATIONS This is a continuation-in-partof application Ser. No. 693,765, filed Dec. 27, 1967, and now abandoned,which is a continuation-in-part of application Ser. No. 605,995, filedDec. 30, 1966, and now abandoned, which is a continuation-in-part ofapplication Ser. No. 462,066, filed June 7, 1965, and now abandoned.

It is an object of this invention to provide a new class of therapeuticcompounds. It is another object of the present invention to providenovel compounds having hypotensive activity. It is a further object ofthe present invention to provide a process for preparing the noveltherapeutic compounds and to provide intermediates useful in thepreparation thereof. It is still a further object of the presentinvention to provide a novel method of treating hypertension.

These and other objects which may appear as the specification proceedsare achieved by this invention which comprises the provision ofcompounds selected from the group consisting of compounds having thefollowing formula (DH-Y-NB wherein NB is a primary or secondary aminoradical and Y is (lower)alkylene; and the pharmaceutically acceptablenontoxic salts thereof.

The pharmaceutically acceptable nontoxic salts include the organic andinorganic acid addition salts, e.g., those prepared from acids such ashydrochloric, sulfuric, sulfamic, tartaric, fumaric, hydrobromic,hydriodic, glyco-lic, citric, maleic, phosphoric, succinic, acetic,nitric, cyclohexylsulfamic, naphthalenesulfonic, and the like.

The term (lower)alkylene as used herein means both straight and branchedchain alkylene radicals containing from 1 to 8 carbon atoms, e.g.methylene, ethylene, octylene, propylene, butylene, isobutylene,t-butylene, amylene, hexylene, Z-ethylhexylene, etc.

The term (lower)alkyl" as used herein 'means both straight and branchedchain aliphatic hydrocarbon radicals containing from 1 to 8 carbonatoms, e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl,amyl, hexyl, 2-ethylhexyl, octyl, etc.

Similarly, where the term (lower) is used as part of the description ofanother group, e.g., (lower)alkoxy, it refers to the alkyl portion ofsuch group which is therefore as described in connection with(lower)alkyl,

The term primary amino radical as used herein refers to a radicalobtained by removing one hydrogen atom attached to the nitrogen atom ofa primary amine, and thus comprises radicals of the formula:

wherein R is selected from the group consisting of (lower)a1kyl,cycloalkyl having from 3 to 7 carbon atoms, inclusive,p-phenylcyclopropyl, benzo'dioxan-Z-methylene, and radicals of theformula (III) R wherein n is a whole integer from 0 to 3 inclusive; andR and R each represent a member selected from the group consisting ofhydrogen, (lower)alkyl, (lower)alk oxy, chloro, bromo, fluoro, iodo,trifluoromethyl, di(lower)alkylamino, (lower) alkylthio, phenyl, phenoxyand benzyl. The term primary amino radical therefore includes forexample, such radicals as methylamino, ethylamino, propylamino,isopropylamino, hexylamino, cyclopropylarnino, cyclopentylamino,cyclohexylamino, cycloheptylamino, phenylamino, benzylamino,p-methoxyphenylamino, o-chlorobenzylamino, benzodioxan-Z-methyleneamino,fl-phenethylamino, 2,4-dimethylphenylamino and the like.

The term secondary amino radical refers to a radical obtained byremoving one hydrogen atom attached to the nitrogen atom of a secondaryamine, and thus comprises radicals of the formula acorn-Q wherein n is awhole integer from 0 to 3 inclusive; and R and R" each representhydrogen, (lower)alkyl, (lower) alkoxy, chloro, bromo, fiuoro, iodo,trifluoromethyl, di

4 3 (lower) alkylamino, (lower)alkylthio, phenyl, phenoxy and benzyl,and when R and R are taken together with wherein R and R each representhydrogen, (lower) alkyl or hydroxy, R represents hydrogen, (lower)alkyl,hydroxy or a radical of the formula (XII) R" wherein R and R eachrepresent a member selected from the group consisting of hydrogen,(lower)alkyl, (lower)alkoxy, chloro, bromo, fiuoro, iodo,trifluoromethyl, di(lower)alkylamino, (lower)alkylthio, phenyl, phenoxyand benzyl; R represents (lower)alkyl, hydroxy or a radical of theformula (XIII) wherein R and R each represent a member selected from thegroup consisting of hydrogen, (lower)alkyl, (lower)alkoxy, chloro,bromo, fluoro, iodo, trifluoromethyl, di(lower)alkylamino,(lower)alkylthio, phenyl, phenoxy and benzyl. The term secondary aminoradical therefore includes for example, such radicals as pyrrolidino,3-hydroxypyrrolidino, piperidino, 4-hydroxypiperidino, 4 phenyl 1,2,5,6tetrahydropyridino, 4- phenylpiperazino, 4 (o methoxy)phenylpiperazino,4- methylpiperazino, morpholino, 2 methylmorpholino, hexamethyleneimino,2,4 dimethylhexamethyleneimino, 4-:phenylpiperidino,1,2,5,6-tetrahydropyridino, dimethylamino, diethylamino, dipropylamino,di-n-butylamino, diisoamylamino, dibenzylamino, diphenylarnino,dicyclopropylamino, dicyclopentylamino, dicyclohexylamino,dicycloheptylamino, N-benzyl N cyclopropylarnino, N- methyl N (ptrifluoromethylphenyl)amino, N-methyl- N (2,4 dimethylphenyl) amino, Nbenzodioxan 2- methylene-N-methylamino and the like.

The compounds of this invention having the structure described inFormula I and some of the compounds of Formula XVIII, i.e. those of theformula (XIV) O -JJH CHgCHr-N N-Q wherein R is (lower)alkyl describedhereinafter, produce a potent and prolonged blood pressure loweringeffect in mammals which makes them useful in the treatment ofhypertension.

Tests of the compounds of the present invention for hypotensive activitywere carried out in rats and dogs. When, for example, N ['y hydroxy 'y(2 dibenzofuryl)butyl] 4 phenyl 1,2,5,6 tetrahydropyridine hydrochloridewas administered orally in rats at dosages of 10 mg./kg., a reduction inarterial blood pressure was obtained of greater than 10% When 2 [4 (omethoxyphenylpiperazino) butyroy11dibenzofuran was administered orallyin dogs at dosages of 20 mg./kg., a reduction in arterial blood pressurewas obtained of greater than 10%.

Some of the compounds of Formula XVIII, i.e. those of the formulawherein R is (lower)alkyl described hereinafter possess sedativeactivity and muscle relaxant activity making them useful as minortranquilizers in mammals.

The muscle relaxant activity of the compounds was determined by pressingthe abdomen and flexing the hind limbs of the treated mouse. Limb toneand grip strength were further checked by placing the mice on a verticalpole. A mouse treated with a muscle relaxant drug shows little if anyresistance to flexing or abdominal tone, and is unable to climb the poleor to maintain itself on the pole. Doses as low as 75 mg./kg. p.o. of apreferred compound Z-[B-(N o methoxyphenyl)piperazino1propionyldibenzofuran in mice produced muscle relaxant activity.

The sedative activity of the compounds was evaluated by the behavioraldepression test. In the behavioral depression test, treated mice areobserved in an undisturbed condition for signs of behavioral depressionand are checked for their reaction to selected auditory, nocicep tiveand tactile stimuli. At the same time, a subjective evaluation ofspontaneous motor activity is made. When, for example, a preferredcompound Z-[fi-(N-o-methoxyphenyl)piperazino]propionyl dibenzofuran wastested, it exhibited sedative activity at doses as low as 75 mg./kg.p.o. The LD for the compound is greater than 3000 mg./kg.

A preferred group of compounds of Formula I are those of the formulawherein R R R and Y are as described above. A more preferred group ofcompounds are those of the formula Rs R12 OH wherein R R R R and Y areas described above.

Representative of the compounds of this invention are (XVII) 1-(Z-dibenzofuryl -2-cyclopropylaminopropanol,

1- (2-dibenzofuryl) -4-diethylaminobutanol,

1- (Z-dibenzofuryl) -2- (4-phenyl- 1,2,5 ,6-tetrahydropyridino) ethanol,

1-(2-dibenzofuryl)-3- (4-phenyl-1,2,5,6-tetrahydropyridino) propanol,

1-(Z-dibenzofuryl)-4-(4-phenyl-1,2,5,6-tetrahydropyridino) butanol,

1- 2-dibenzofuryl -2- 4-phenylpiperazino) ethanol,

1- (Z-dibenzofuryl) -2- (4-o-methoxyphenylpiperazino) ethanol,

1- (Z-dibenzofuryl) -3- (4-o-methoxyphenylpiperazino) propanol,

1- Z-dibenzofuryl -4-(4-o-methoxyphenylpiperazino) butanol,

1- (Z-dibenzofuryl) -4-morpholinobutanol,

1-(2-dibenzofuryl -4-( 1,2,5 ,G-tetrahydropyridino) butanol,

1-(2-dibenzofuryl -4-piperidinobutanol,

1-(Z-dibenzofuryl)-4-pyrrolidinobutanol,

1- Z-dibenzofuryl) -4-hexamethy1eneiminobutanol,

1- (Z-dibenzofuryl) -4-(3-hydroxypyrrolidino butanol,

1-(2-dibenzofuryl) -2- (4-2,4-dimethylphenylpiperidino) ethanol and 1-(Z-dibenzofuryl) -4- (2,4,6-trimethylpiperazino butanol.

The compounds of the present invention are prepared according to thefollowing general procedure which consists of reducing an aminoketone ofthe formula wherein Y and NB are as represented above, to anaminoalcohol of Formula I. The reduction may be effected chemically orby catalytic means. Some of the chemical reducing agents which may beused are sodium borohydride in a hydroxylic solvent such as methanol orethanol or lithium aluminum hydride in anhydrous ethyl ether ortetrahydrofuran. Catalysts such as platinum, platinum oxide,platinum-on-a-carrier and hydrogen at elevated pressures (30-3,000p.s.i.) are capable of reducing the aminoketone of Formula XVIII to theaminoalcohol of Formula I. In the case of an unsaturated aminoketone(e.g., where NB is 4-phenyl-1,2,5,6-tetrahydropyridino or1,2,5,G-tetrahydropyridino), the preferred method of reduction is thesodium borohydride procedure.

The novel aminoketones of Formula XVIII, which are intermediates for thepreparation of the aminoalcohols of this invention (Formula I), areconsidered a part of the present invention and are prepared by thefollowing series of reactions.

(A) Dibenzofuran is reacted with a compound of the formula (XVIII)wherein X is a reactive halogen such as chloro, bromo or iodo, and Y isas described above, in the presence of a Lewis acid, such as aluminumchloride and in the presence of a nonreactive solvent such as benzene toproduce a haloketone of the formula ELY-x wherein X and Y are asdescribed above. The foregoing described reaction is the Friedel-Craftsreaction, and may be represented as follows:

wherein X and Y are as described above.

Representative of the haloketones formed in this manner are 2-(Z-chloroacetyl) dibenzofuran,

2- 3-chloropropionyl dibenzofuran,

2- 4-chlorobutyroyl dibenzofuran,

2- (3-bromobutyroyl dibenzofuran, and 2- 2-chloropropiony1)dibenzofuran.

(B) Amination of the haloketone prepared in Reaction A with a primary orsecondary amine of the formula HNB wherein N3 is as described above, ina nonreactive solvent such as dimethylformamide, methylisobutylketone,dimethylsulfoxide and toluene in the presence of an acid acceptor suchas potassium carbonate, aminopyrine, N-ethyl-N-butylaniline and pyridineand preferably a catalyst such as potassium iodide produces the desiredaminoketone of Formula XVIII. This reaction may be represented asfollows:

wherein X, Y and NB are as described above.

Some of the amines which may be used in this reaction are Representativeof the aminoketones formed in this manner are 2- (3-isopropylaminopropionyl) dibenzofuran,

2- 3 -}8-phenethylaminopropionyl dib enzofuran,

2- (4-pip eridinobutyroyl) dibenzofuran,

2- [4- (4-phenyl-1,2,5,6-tetrahydropyridino)butyroyl] dib enzofuran,

2- 3- (4-phenylpiperazino) propionyl] dib enzofuran,

2- [4- (4-o-methoxypheny1pip erazino butyroyl] dib enzofuran,

2- [4- 2-benzodioxanmethyleneamino) butyroyl] dibenzofuran,

2- [4- (N-2-b enzenedioxanmethylene-N-methylamino butyroyl]dibenzofuran,

2- 3-cyclopropylaminopropionyl) dibenzofuran,

2- Z-isopropylaminoacetyl dib enzofuran,

2- (Z-fi-phenylcyclopropylaminoacetyl) dibenzofuran,

2- Z-B-phenylisopropylamino acetyl dibenzofuran and 2- [2- (13-3,4-methylenedioxyphenylisopropylamino) acetyl] dibenzofuran.

The novel aminoketones of Formula XVIII wherein Y is -CH3CHgwhich areintermediates for the preparation of the corresponding aminoalcohols ofthis invention (Formula I) are also prepared by the following series ofreactions.

O yJ-CHgCHPNB NB is as described above.

In essence, it involves a Friedel-Crafts reaction of dibenzofuran withacetyl chloride to produce the 2-acetyldibenzofuran. The latter is thensubjected to a Mannich reaction with dimethylamine and the Mannich basequaternized with methyl iodide. The quaternary ammonium salt is allowedto react with the corresponding amine (H'NB) to yield the-desiredaminoketone.

The reaction is particularly useful for producing the novel aminoketonesof Formula XV i.e. where HNB is HN N wherein R is (lower) alkyl whichpossess sedative and muscle relaxant activity and are useful as minortranquilizers.

The starting materials used in the processes described herein arecompounds which are either commercially available, well known in theart, or easily'prepared in accordance with standard organic procedurespreviously described in the chemical literature. a

The compounds of this invention may be administered as the free bases orin the form of their nontoxic addition salts. They may be compounded andformulated into pharmaceutical preparations in unit dosage form for oralor parenteral administration with organic or inorganic solid materialsor liquids which are pharmaceutically acceptable carriers. Thecompositions may take the form of tablets, powder granules, capsules,suspensions, solutions and the like. Such compositions are consideredwithin the scope of this invention.-

The compositions of this invention when administered orally orparenterally, in an effective amount are efiective in the treatment ofhypertension and in producing sedation and muscle relaxation in mammals.The novel compounds 8 of this invention may be advantageouslyadministered at a dosage range from about 5 mg./kg. to about 1000mg./kg. per day, preferably in subdivided amounts on a 2 to 4 times aday regimen. Typically treatment in man is begun at about A the animalminimum effective dose and then increased or decreased as required.

The following examples are intended to illustrate the inventiondescribed herein without unduly restricting it.

EXAMPLE 1 Preparation of 2-(4-chlorobutyroyl)dibenzofuran o h-omomom-oiA mixture of dibenzofuran (70 gm., 0.43 mol) and 500 ml. of dry benzenewas treated with anhydrous aluminum chloride (61 gm., 0.46 mol) and then4-chlorobutyroyl chloride (65 gm., 0.46 mol). After 5 minutes, avigorous reaction began which required cooling. The mixture was allowedto stand at room temperature for 5 hours and then poured onto crushedice. After 0.5 hour, ml. of concentrated hydrochloric acid was added.The mixture was stirred for 1 hour, and then the organic layer wasremoved, washed with potassium carbonate solution and.

water, and dried over calcium chloride. The solvent was removed undervacuum to yield 101 gm. of an oil which solidified on cooling. Thismaterial was recrystallized from 300 ml. of methanol to give 62 gm. ofthe product, 2-(4- chlorobutyroyl) dibenzofuran, MJ. 83-90 C.

EXAMPLE 2 Preparation of 2- ['y- (4-phenyl- 1,2,5,6-tetralhydropyridino) butyroyl] dibenzofuran EXAMPLE 3 Preparation ofN-[' -hydroxy-v-(2-dibenzofuryl)butyl]-4-phenyl-1,2,5,6-tetrahydropyridine hydrochloride [Also-known herein as1-(2-dibenzofuryl)-4-(4-phenyl- 1,2,5 ,6-tetrahydropyridino butanol] onlH-CHiCHzCHrN --no1 A mixture of 2-['-(4-phenyl-1,2,5,6-tetrahydropyridino)butyroyl]dibenzofuran (5 gm.,0.012 mol) and sodium borohydride (1 gm., 0.025 mol) in dry ethanol wasrefluxed for 5 hours, then allowed to stand for 48 hours.

The solvent was removed, and 40 ml. of water was added. The product wasfiltered, washed with water, and recrystallized from ethanol to give 4gm. of N-[y-hydroxy-q- (2dibenzofurynbutyl]-4-phenyl-1,2,5,6-tetrahydropyridine, M.P. 120-122 C.A solution of 2.8 gm. of the compound in 10 ml. of ethanol was thentreated with 5 ml. of 2.08 N ethanolic hydrochloric acid rapidly. Thesolution cleared, and after 2 minutes the N-[-hydrQXy-y-(Z-dibenzofuryl)butyl]-4-phenyl-1,2,5,6-tetrahydropyridinehydrochloride crystallized, M.P. 181-1 82 C.

EXAMPLE 4 Preparation of 2-(4-piperidinobutyroyl)dibenzofuranhydrochloride A mixture of piperidine (4.5 gm., 0.05 mol), potassiumcarbonate (7 gm., 0.05 mol), potassium iodide (9 gm., 0.05 mol),2-(4-chlorobutyroyl)dibenzofuran (13.6 gm., 0.05 mol), and 150 ml. ofdimethylformamide was refluxed (temperature: 142 C.) for 24 hours, thenpoured into 500 ml. of water. After 2 hours, the aqueous solution wasextracted with ether, the ether layer was washed with water, dried, andevaporated to yield 14 gm. of a dark oil. This was purified by formingthe 2-naphthalene sulfonate in hot ethanol. This gave 11 gm. of2-(4-piperidinobutyroyDdibenzofuran 2-naphthalene sulfonate salt, M.P.195-196.5 C., which was converted to 5.5 gm. of the pure free base.2-(4-piperidinobutyroyl)dibenzofuran hydrochloride was made, andrecrystallized from ethanol to give the pure product, M.P. 235-236 C.

Analysis.-Calcd. for C H ClNO (percent): C, 70.48; H, 6.76; N, 3.91; Cl,9.91. Found (percent): C, 69.57; H, 6.68; N, 3.99; Cl, 10.16.

EXAMPLE 5 Preparation of 1-(2-dibenzofuryl)-4-piperidinobutano1 but -OH.The base was converted to the hydrochloride salt by treating the ethanolsolution ml. at OH) of the base with 13 ml. of 0.77 N ethanolichydrochloric ac1d (.01 mol) and adding heptane, and scratching. Theproduct 1-(2-dibenzofuryl)-4-piperidinobutanol hydrochloridecrystallized, weight 2.6 gm. M.P. 189-190 (2.; after recrystallizationfrom ethanol, M.P. 190-1905 C.

EXAMPLE 6 When, in the procedure of Example 2, 4-phenyl-l,2,5,6-tetrahydropyridine is replaced by an equal molar amount of 1,2,5,6-tetrahydropyridine, 2-hydroxy-1,2,5,6-tetrahydropyr1d1ne,

10 4-methy1-1,2,5,6-tetrahydropyridine, 5 -methyl-1,2,5,6-tetrahydropyridine, 2,5-dimethyl-1,2,5,6-tetrahydropyridine,5-octyl-1,2,5,6-tetrahydropyridine, 6-propyl- 1,2,5,6-tetrahydropyridine, 2-hydroxy-5-methyl-1,2,5,6-tetrahydropyridine,3-methyl-1,2,5,6-tetrahydropyridine,4-4-methoxyphenyl-1,2,5,6-tetrahydropyridine,4-3-chlorophenyl-1,2,5,6-tetrahydropyridine,4-2-iodophenyl-1,2,5,6-tetrahydropyridine,4-4-methylphenyl-1,2,5,6-tetrahydropyridine,4-2,4-dirnethoxyphenyll,2,5,6-tetrahydr0pyridine,4-4-dimethylaminophenyl-1,2,5 ,G-tetrahydropyridine,4-4-phenylphenyl-1,2,5,6-tetrahydropyridine,4-4-methylthiophenyl-1,2,5,6-tetrahydropyridine,4-2-fiuorophenyl-1,2,5,6-tetrahydropyridine,4-3-benzylphenyl-1,2,5,6-tetrahydropyridine,4-4-trifluoromethylphenyl-1,2,5,6-tetrahydropyridine,2-methyl-4-phenyl-1,2,5 ,6-tetrahydropyridine,4-4-bromophenyl1,2,5,6-tetrahydropyridine,4-4-phenoxyphenyl-1,2,5,6-tetrahydropyridine,2,6-dimethyl-4-phenyl-1,2,5,6-tetrahydropyridine,4-hydroXy-l,2,5,6-tetrahydropyridine, morpholine, 2-hydroxymorpholine,2,5-dimethylmorpholine, B-methylmorpholine, Z-hexylmorpholine,4-methylpiperidine, 2,6-diethylpiperidine, 4-hydroxypiperidine,4-phenylpiperidine, 4-4-chlorophenylpiperidine, 3-butylpiperidine,4-2-bromophenylpiperidine, 4-phenyl-4-hydroxypiperidine,4-3-iodophenylpiperidine, 4-4-trifiuoromethylphenylpiperidine,4-2,5-dimethylphenylpiperidine, 4-3-ethoxyphenylpiperidine,4-3-dimethylaminophenylpiperidine, 4-4-fiuorophenylpipe1idine,4-4-phenylphenylpiperidine, 4-4-phenoxyphenylpiperidine,4-4-benzylphenylpiperidine, 4-4-methylthiophenylpiperidine,4-2-methoxyphenylpiperidine, 4-2-propoxyphenylpiperidine,2,5-dimethyl-4-phenylpiperidine,3-hydroxy-4-4-trifluoromethylphenylpiperidine, hexamethyleneimine,3-methylhexamethyleneimine, 4-hydroxyhexamethyleneimine,3,6-diethylhexamethyleneimine, 2-hydroxyhexamethyleneimine, pyrrolidine,Z-methylpyrrolidine, 2-hexylpyrrolidine, 3-hydroxypyrrolidine,2-hydroxy-3 -methylpyrrolidine, 2,4-dimethylpyrrolidine,4-methylpiperazine, 4-hydroxypiperazine, 4-phenylpiperazine,4-2-methoxyphenylpiperazine, 2-hydroxypiperazine,2,6-dimethylpiperazine, 4-4-trifluoromethylphenylpiperazine,4-2-chlorophenylpiperazine, 4-3-bromophenylpiperazine,4-2-fiuorophenylpiperazine, 4-2-iodophenylpiperazine, 4-4-methylphenylpp 4-3-methylthiophenylpiperazine,

1-(2-dibenzofuryl)-4- (di-benzylamino)butanol,1-(Z-dibenzofuryl)-4-(phenethylamino)butanol, 1-(2-dibenzofuryl)-4-(4-trifluoromethylphenylamino) butanol,1-(2-dibenzofuryl)-4-(N-ethyl-N-2,4-diethylpheny1- amino)butanol,1-(2-dibenzofuryl)-4-(phenylisopropylarnino)butanol,1-(Z-dibenzofuryl)-4-(2-methoxybenzylamino)butanol,1-(2-dibenzofuryl)-4-(2-bromophenylamino)butanol, 1-(2-dibenzofuryl)-4-(3-fluorophenylamino)butanol,1-(2-dibenzofuryl)-4-(2-iodophenylamino)butanol, 1-(2-dibenzofuryl)-4-[N-benzyl-N-(4-phenylphenyl) amino] butanol,1-(Z-dibenzofuryl)-4-(3-phenoxyphenylamino)butanol,1-(2-dibenzofuryl)-4-(4-benzylphenylamino)butanol,

and 1-(2-dibenzofuryl)-4- (4-ethylthiophenylamino)butanol,

respectively.

EXAMPLE 12 When, in the procedure of Example 3, 2-[ -(4-phenyl- 1,2,5,6tetrahydropyridino)butyroyl] dibenzofuran is replaced by an equal molaramount of each of the products of Example 9, there are obtained,

1-(2-dibenzofuryl) -2-(4-phenyl-1,2,5,6-tetrahydropyridino) ethanol,

l-(2-dibenzofuryl)-3- (4-pheny1-1,2,5,6-tetrahydropyridino propanol,

1- (Z-dibenzofuryl)-2-(4-phenyl-1,2,5,6-tetrahydropyridino)butano1,

1-(2-dibenzofuryl)-3-(4-phenyl-1,2,5,6-tetrahydropyridino butanol,

1- (Z-dibenzofuryl) -2- (4-phenyl-1,2,5,6-tetrahydropyridino) propanol,

I-(Z-dibenzofuryl)-6-(4-phenyl-1,2,5,6-tetrahydropyridino hexanol, and

1- (Z-diberrzofuryD-S- (4-phenyl-1,2,5,6-tetrahydropyridino octanol,respectively.

EXAMPLE 13 Preparation of 2-[4-(o-methoxyphenylpiperazino) butyroyl] dibenzofuran (percent) C,

75.67; H, 6.59; N, 6.54. Found (percent): C, 75.60; H,

While this invention has been described and exemplified in terms of itspreferred embodiment, those skilled in the art will appreciate thatmodifications can be made without departing from the spirit and scope ofthis invention.

18 EXAMPLE 14 Preparation of 2-[fi-(N'-o-methoxyphenyl)piperazino]propionyldibenzofuran 0 CHaO By the procedure of Example 1dibenzofuran was re- Alternate procedure for preparation of2-[B-(N-omethoxyphenyl )piperazino] prop ionyldibenzofuran (A) 2-acetyldibenzofuran: This compound was obtained by a standardFriedel-Crafts reaction as described under Example 1 by reactingdibenzofuran with acetyl chloride and aluminum chloride. The productwhich distilled at 135-145 C./0.08 mm. weighed 133 g. (63% yield). Thesolid gave M.P. 67-69 C. (lit. 81 C.) but one recrystallization frommethanol gave M.P. 74 75.5 C. with no loss. References: -N.P. Buii-Hoyand R. Royer, Rec. trav. chim. 69, 861 (1950); CA. 45, 3832 (1951);Galewsky Ann., 264, 189; Beilstein 17, 363 (1933).

(B) B-Dimethylamino 2 propionyl-dibenzofuran hydrochloride: A mixture ofZ-acetyl-dibenzofuran (21.0 g., 0.1 M), dimethylamine hydrochloride (8.2g., 0.1 M), paraformaldehyde (3.0 g., 0.1 M) and acetic acid (30 ml.)was heated on the steam bath for 1.5 hours, then concentrated. Theresidue was triturated with acetone (50 ml.) to give a white solid. Theproduct was recrystallized from ethanol; when dry, it weighed 16.0 g.(53% yield); M.P. 195-196 C. An infrared spectrum showed a strong peakat 5.98 A sample was converted to the base to give a solid which afterrecrystallization from isopropanol melted at -86 C.

Analysisr- Calcd. for C H O N (percent): C, 76.38; H, 6.41; N, 5.24.Found (percent): C, 76.13; H, 6.25; N, 5.54.

(C) B-Dimethylamino-2propionyl-dibenzofuran methiodide:8-Dimethylamino-2-propionyl-dibenzofuran hydrochloride (12.5 g., 0.0411M) was placed in dilute sodium carbonate solution and extracted withether. The ether extract was dried over anhydrous potassium carbonate.The dry ethereal extract was added dropwise under anhydrous conditionsto a solution of methyliodide (13.96 g., 0.098 M) in ether (50 ml.) overa period of 45 minutes. The mixture was stirred at room temperature for64 hours. Then the white solid was collected; when dry, it weighed 146g. (87;% yield), M.P. ZOO-202 C.

(D) 2 [fi-(N'-o-methoxyphenyl)piperazino]propionyldibenzofuran: Amixture of the quaternary salt, B-dimethylamino 2 propionyl-dibenzofuranmethiodide (7.0 g., 0.0171 M), N-(o-methoxyphenyl)piperazine (3.28 g.,0.0171 M), anhydrous sodium carbonate (3.62 g., 0.0342 M) anddi-methylformamide (40 ml.) was stirred by means of a vibromixer. Thestirred system was swept with nitrogen for 7.5 hours. The mixture wasthen poured in cold water (300 ml.). A white solid separated; it wascollected by filtration, washed with water and recrystallized fromethanol to give 4.40 g. (62% yield), M.P. 147.5-14'8.5

C. An infrared spectrum showed peaks at 6.0 and 8.06. A sample purifiedfor analysis melted at l49-l49.5 C.

Analysis.-Calcd. for C H O N (percent): C, 75.34; H, 6.32; N, 6.76.Found (percent): C, 75.27; I-I, 6.14; N, 6.82.

EXAMPLE 16 When in the procedure of Example 15,N-(o-methoxyphenyl)piperazine is replaced by 0.0171 mole of N-(o-ethoxyphenyDpiperazine N- (o-propoxyphenyl)piperazine N-(o-isopropoxyphenyl)piperazine N-(o-butoxyphenyl)piperazine and N-(o-t-butoxyphenyl) piperazine there are obtained While this inventionhas been described and exemplified in terms of its preferred embodiment,those skilled in the art will appreciate that modifications can be madewithout departing from the spirit and scope of this invention.

We claim:

1. A compound selected from the group consisting of compounds of theformula wherein:

R and R each represent hydrogen, (Iower)alkyl droxy,

R represents hydrogen, (lower)alkyl, hydroxy or a radical of the formulaor hy- R and R each represent a member selected from the groupconsisting of hydrogen, (lower)alkyl, (lower)- 20 alkoxy, chloro, bromo,fluoro, iodo, trifluoro'methyl, di- (lower)alkylamino, (lower)alkylthio,phenyl, phenoxy and benzyl, and Y is (lower)alky-lene; and thepharmaceutically acceptable nontoxic salts thereof.

2. A compound of claim 1 having the formula wherein: R and R eachrepresent hydrogen, (lower)alkyl or hydroxy and Y is (lower)alkylene.

3. The compound of claim 1 having the formula OH (HCH;CHgCHgN 4. Thepharmaceutically acceptable nontoxic salts of the compound of claim 3.

5. The compound of claim 1 having the formula on oH-cmomcHr-U 6. Thecompound of claim 1 having the formula References Cited FOREIGN PATENTS687,892 2/1953 Great Britain 260346.2 703,257 2/1954 Great Britain260-346.2

HENRY R. JILES, Primary Examiner G. T. TODD, Assistant Examiner us. 01.XJR.

260247.7G, 268 TR, 297 T, 326.5 CA, 340.3, 346.2 M; 424248, 250, 263,267, 274, 285

